Journal for immunotherapy of cancer, 2024-05, Vol.12 (5), p.e009013
2024
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- Autor(en) / Beteiligte
- Titel
- Developing a membrane-proximal CD33-targeting CAR T cell
- Ist Teil von
- Journal for immunotherapy of cancer, 2024-05, Vol.12 (5), p.e009013
- Ort / Verlag
- England: BMJ Publishing Group Ltd
- Erscheinungsjahr
- 2024
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- BackgroundCD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking.MethodsWe developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice.ResultsWe found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both low antigen density and clinically relevant patient-derived xenograft models. Increased activation and enhanced polyfunctionality led to enhanced efficacy.ConclusionsShowing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2051-1426eISSN: 2051-1426DOI: 10.1136/jitc-2024-009013Titel-ID: cdi_doaj_primary_oai_doaj_org_article_b42d94a937d841e2987bd9a5c7486879
- Format
- –
- Schlagworte
- Adoptive cell therapy - ACT, Amino acids, Animals, Antibodies, Antigens, Blood, Cell Line, Tumor, Chimeric antigen receptor - CAR, Flow cytometry, Humans, Immune Cell Therapies and Immune Cell Engineering, Immunoglobulins, Immunotherapy, Immunotherapy, Adoptive - methods, Leukemia, Leukemia, Myeloid, Acute - immunology, Leukemia, Myeloid, Acute - therapy, Lymphocytes, Mice, Penicillin, Proteins, Receptors, Chimeric Antigen - immunology, Receptors, Chimeric Antigen - metabolism, Sialic Acid Binding Ig-like Lectin 3 - immunology, Sialic Acid Binding Ig-like Lectin 3 - metabolism, Stem cell transplantation, T cell, T-Lymphocytes - immunology, Xenograft Model Antitumor Assays